Immunologic reconstitution during PEG-ADA therapy in an unusual mosaic ADA deficient patient.
We report detailed genetic and immunologic studies in a patient diagnosed with adenosine deaminase (ADA) deficiency and combined immune deficiency at age 5 years. At the time of diagnosis, although all other lymphocyte subsets were depleted, circulating CD8(+) T cells with a terminally differentiated phenotype were abundant and expressed normal ADA activity due to a reversion mutation in a CD8(+) T cell or precursor. Over the first 9 months of replacement therapy with PEG-ADA, the patient steadily accumulated mature naïve CD4(+) and CD8(+) T cells, as well as CD4(+)/FOXP3(+) regulatory T cells, consistent with restoration of a functional cellular immune system. While CD19(+) naïve B cells also accumulated in response to PEG-ADA therapy, a high proportion of these B cells exhibited an immature surface marker phenotype even after 9 months, and immunization with neoantigen bacteriophage varphiX174 demonstrated a markedly subnormal humoral immune response. Our observations in this single patient have important implications for gene therapy of human ADA deficiency, as they indicate that ADA expression within even a large circulating lymphocyte population may not be sufficient to support adequate immune reconstitution. They also suggest that an immature surface marker phenotype of the peripheral B cell compartment may be a useful surrogate marker for incomplete humoral immune reconstitution during enzyme replacement, and possibly other forms of hematopoietic cell therapies.
Liu
Ping
P
Department of Pediatrics, University of Washington and Seattle Children's Hospital Research Institute, Seattle, WA, USA.
Santisteban
Ines
I
Burroughs
Lauri M
LM
Ochs
Hans D
HD
Torgerson
Troy R
TR
Hershfield
Michael S
MS
Rawlings
David J
DJ
Scharenberg
Andrew M
AM
D000243:Adenosine Deaminase / Q000097:blood / Q000172:deficiency* / Q000276:immunology / Q000627:therapeutic use; D016175:B-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D010584:Bacteriophage phi X 174 / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D002675:Child, Preschool; D006801:Humans; D008297:Male; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
D000243:Adenosine Deaminase; C051409:pegademase bovine